One-pot preparation method and application of S-217622 intermediate
Through the one-pot preparation method, multiple stage reactions are carried out using specific raw materials and alkaline conditions, the low yield and chemical pollution problems of the existing Ensetvir synthesis route are solved, and efficient and environmentally friendly intermediate preparation is achieved.
Patent Information
- Application Number
- CN202211724227.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-30
- Publication Date
- 2025-04-15
- Estimated Expiration
- 2042-12-30
AI Technical Summary
The existing synthetic route of Ensetway (S-217622) has problems with low yields caused by multi-step reactions, acid-base condition switching and chemical pollution in industrial production.
A one-pot preparation method is adopted, and the S-217622 intermediate is directly obtained by conducting a multi-stage reaction under alkaline conditions by 2-ethylisothiourea or its salt, N,N-carbonyldiimidazole (CDI), methyl-triazole benzylamine or its salt, and the intermediate purification treatment is omitted.
The multi-step reaction has been simplified, the reaction conditions are mild, and the total yield is increased to 53%, reducing chemical pollution and improving production efficiency.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis technology, and specifically relates to a one-pot preparation method and application of a S-217622 intermediate. Background Art
[0002] Ensetivir (S-217622) is considered to be the first orally active, non-covalent, non-peptide SARS-CoV-2 3CL protease inhibitor, which addresses the shortcomings of peptide covalent inhibitors and has a favorable drug metabolism and pharmacokinetic (DMPK) profile.
[0003] The compound shown in formula I is a key intermediate of Ensetevir. Chinese patent CN15260166A discloses a synthesis method as follows:
[0004]
[0005] Specifically, the raw material is alkylated at the 1-position N under alkaline conditions, then de-tert-butylated under acidic conditions, and then reacted with chloromethyltriazole under alkaline conditions again to obtain the product.
[0006] In the above synthesis scheme, the tert-butyl group as a protecting group must be removed first in the alkylation reaction of position 3. However, the deprotection condition is acidic, and the alkylation reaction is alkaline. The introduction of this protecting group will inevitably cause the reaction to switch between alkaline and acidic conditions. The yield of the last step of the alkylation reaction is only 45%, which leads to the total yield of the four steps as low as 28%.
[0007] Another synthesis route is disclosed in Chinese patent CN114644621A, as shown below:
[0008]
[0009] In this scheme, the alkylation of N at position 3 (compound of formula II) is first performed, and then the alkylation of N at position 1 is performed, thereby avoiding the tert-butyl protection and deprotection of N at position 3, that is, overcoming the disadvantage of alternating acid-base reaction environments. However, it uses a raw material, 1-methyl-3-isocyanate methyl-1H-1,2,4-triazole, which has no commercial source because the isocyanate group is extremely unstable and the use range of the raw material is relatively narrow. If this route is implemented, it is necessary to synthesize this raw material first. Example 1 of the document also provides a synthesis method. Triphosgene is required in the reaction, and it is difficult to purify, and the subsequent reaction is carried out as an oily substance. It can be seen that this route also has less ideal links in industrial production.
[0010] Therefore, developing a simple, green and efficient synthesis scheme to prepare the key intermediate compound represented by Formula I is of great significance and value to Ensetivir. Summary of the invention
[0011] The present invention provides a one-pot preparation method and application of an S-217622 intermediate, which is used to solve the problem that the post-treatment of the current synthesis route is time-consuming and labor-intensive, and a large class of chemical pollutants are used or generated.
[0012] In order to solve the above technical problems, the technical solution of the present invention is: a one-pot preparation method of the S-217622 intermediate, wherein the S-217622 intermediate is a compound of formula II, which uses 2-ethylisothiourea or a salt thereof (formula III) as a starting material, adds an alkaline reagent to a reaction solvent, and adds N,N-carbonyldiimidazole (CDI), methyl-triazole benzylamine or a salt thereof (formula IV compound) and N,N-carbonyldiimidazole (CDI) in stages to react, and finally obtains a compound of formula II.
[0013] Optionally, the preparation method is divided into three stages of feeding, specifically including:
[0014] In the first stage, the compound of formula III, the first batch of CDI and the first batch of alkaline reagent are added to the solvent, and the second stage is entered after the reaction of the compound of formula III is complete;
[0015] In the second stage, a second batch of alkaline reagent and the compound of formula IV are added, and after the compound of formula IV is completely reacted, the third stage is entered;
[0016] In the third stage, the second batch of CDI and the third batch of alkaline reagent are added to react completely to obtain the product compound of formula II.
[0017] Optionally, the three batches of alkaline reagents are the same and are selected from N,N-diisopropylethylamine (DIPEA) or 1,8-diazabicycloundec-7-ene (DBU).
[0018] Optionally, the molar ratio of the first batch of CDI, the first batch of alkaline reagent and the compound of formula III is (1.0-1.2):(1-1.2):1.
[0019] This step of reaction can be relatively thorough, ensuring that there is no excessive CDI residue, so as to ensure that the second stage reaction will not produce too many impurities due to CDI, affecting the yield and subsequent reactions.
[0020] Optionally, the feeding ratio of the second batch of alkaline reagent and the compound of formula IV is calculated based on the compound of formula III, and the molar ratio of the second batch of alkaline reagent, the compound of formula IV and the compound of formula III is (2.0-2.5):(0.9-1.1):1.
[0021] The compound of formula IV is prone to self-condensation under the reaction conditions to produce by-products, so the amount of the alkaline reagent and the compound of formula IV must be controlled to ensure a high yield.
[0022] Optionally, the feeding ratio of the second batch of CDI and the third batch of alkaline reagent is calculated based on the compound of formula III, and the molar ratio of the second batch of CDI, the third batch of alkaline reagent and the compound of formula III is (1-1.5):(2-2.5):1.
[0023] Optionally, the solvent is selected from N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or acetonitrile (MeCN).
[0024] Optionally, the compound of formula III is 2-ethylisothiourea hydrobromide, and the compound of formula IV is methyl-triazole benzylamine hydrochloride.
[0025] The present invention also provides a one-pot preparation method for another intermediate of S-217622, wherein the intermediate of S-217622 is a compound of formula I. When the compound of formula II is obtained by the above preparation method, an inorganic base and a 2,4,5-trifluoro-halogenated benzyl compound (formula V) are directly added to the reaction system without post-treatment to carry out an alkylation reaction to obtain the compound of formula I.
[0026] Optionally, the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, preferably sodium carbonate or potassium carbonate.
[0027] Optionally, the compound of formula V is 2,4,5-trifluoro-benzyl chloride or 2,4,5-trifluoro-benzyl bromide.
[0028] The present invention also provides the use of the above-mentioned S-217622 intermediate in the preparation of S-217622 compound.
[0029] Compared with the prior art, the technical solution provided by the present invention has the following advantages: through reasonable material selection and feeding, multi-step reactions can be carried out under similar reaction conditions, the reaction conditions are mild and easy to operate, and most importantly, the purification process in the middle of each step of the reaction is completely omitted, the total yield is as high as 53%, which saves time and effort and is environmentally friendly, and has ideal application prospects. DETAILED DESCRIPTION
[0030] For ease of understanding, the one-pot preparation method and application of the S-217622 intermediate are described below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.
[0031] Unless otherwise noted, all commercially available materials and solvents were used directly without further purification. Thin layer chromatography (TLC) was performed on 0.25 mm silica gel F-254 plates. 1H NMR and 13C NMR data were recorded using a Bruker spectrometer (400 MHz) using TMS as an internal standard, and ESI mass spectra were measured on a THERMO LTQ.
[0032] Example 1 One-pot preparation of compound II
[0033]
[0034] DBU (1.1 molar equivalents) and CDI (1.1 equivalents) were added to a DMF solution of 2-ethylisothiourea hydrobromide (1 molar equivalent). After TLC monitoring showed that the reaction of the compound of formula III was complete, methyl-triazole benzylamine hydrochloride (1.0 molar equivalent) and DBU (2.2 equivalents) were added to the reaction, and the mixture was stirred at room temperature overnight. Finally, CDI (1.2 molar equivalents) and DBU (2.2 equivalents) were added to the reaction, and the mixture was stirred at 110°C for 3 hours. After the reaction was complete by TLC, the compound of formula II was obtained by post-treatment.
[0035] Example 2 One-pot preparation of compound of formula I
[0036]
[0037] DIPEA (1.1 molar equivalents) and CDI (1.1 equivalents) are added to a DMF solution of 2-ethylisothiourea hydrobromide (1 molar equivalent). After the TLC compound of formula III is completely reacted, methyl-triazole benzylamine hydrochloride (1.0 molar equivalent) and DIPEA (2.2 equivalents) are added to the reaction, and stirred at room temperature overnight. Then, CDI (1.2 molar equivalents) and DIPEA (2.2 molar equivalents) are added to the reaction, and stirred at 110° C. for 3 hours. After the TLC reaction is complete, 2,4,5-trifluoro-benzyl bromide (1.2 molar equivalents) and potassium carbonate (2.2 molar equivalents) are added, and the mixture is heated to about 90° C. and stirred. After the TLC reaction is complete, the mixture is cooled, post-treated, and purified to obtain the compound of formula I with a purity of 92%. The total yield from the compound of formula III to the compound of formula I is 53%.
[0038] Comparative Example 1
[0039] The difference from Example 2 is that the base in the last step of the reaction is replaced with DIPEA, and no product is generated. Further addition of DMAP as a catalyst still results in no product being generated.
[0040] Example 3 Preparation of S-217622
[0041] The compound of formula I (1 molar equivalent), 6-chloro-2-methyl-2H-indazole-5-amine (1.5 molar equivalents), and acetic acid (10 molar equivalents) were refluxed in tert-butyl alcohol solvent for 6-8 hours. After the reaction was complete, the mixture was cooled, post-treated, and purified to obtain S-217622. EI-MS m / z: 532 + .
[0042] Embodiment 4-6
[0043] The main difference from Example 1 is that different alkaline reagents and solvents are used, and the specific selection and results are summarized in Table 1. However, when the alkaline reagent is triethylamine, the reaction temperature is reduced to 90° C., and the reaction temperature needs to be adjusted according to the boiling point of the solvent.
[0044] Comparative Examples 2-5
[0045] The difference from Example 1 is that different alkaline reagents and solvents are used. The specific selections and results are summarized in Table 1.
[0046] The comparative experimental results are shown in Table 1, where the reaction intermediate VI is monitored by TLC spot plate, while the trace product of intermediate II is known by TLC spot plate, and the remaining yields are the yields calculated using 2-ethylisothiourea hydrobromide as the raw material after purification.
[0047] Table 1
[0048]
[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. Although the present invention has been described in detail with reference to the above embodiments, a person skilled in the art should understand that the technical solutions described in the above embodiments can still be modified, or some or all of the technical features can be replaced by equivalents, and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A one-pot preparation method of S-217622 intermediate, characterized in that: The S-217622 intermediate is a compound of formula II, which uses 2-ethylisothiourea or its salt compound as a starting material, adds an alkaline reagent to a reaction solvent, and adds CDI, methyl-triazole benzylamine or its salt and CDI in stages to react, and finally obtains a compound of formula II The alkaline agent is selected from DIPEA or DBU, and the solvent is selected from DMF, DMSO or MeCN.
2. The preparation method according to claim 1, characterized in that: The preparation method is divided into three stages of feeding, specifically including: In the first stage, a compound of formula III, a first batch of CDI and a first batch of alkaline reagent are added to the solvent, and the second stage is entered after the compound of formula III reacts completely. The compound of formula III is 2-ethylisothiourea bromate; In the second stage, a second batch of alkaline reagent and a compound of formula IV are added, and after the compound of formula IV is completely reacted, the third stage is entered, wherein the compound of formula IV is methyl-triazole benzylamine hydrochloride; In the third stage, the second batch of CDI and the third batch of alkaline reagent are added to react completely to obtain the product compound of formula II.
3. The preparation method according to claim 2, characterized in that: The molar ratio of the first batch of CDI, the first batch of alkaline reagent and the compound of formula III is (1-1.2): (1-1.2):
1.
4. The preparation method according to claim 2, characterized in that: The feeding ratio of the second batch of alkaline reagent and the compound of formula IV is calculated based on the compound of formula III, and the molar ratio of the second batch of alkaline reagent, the compound of formula IV and the compound of formula III is (2.0-2.5):(0.9-1.1):
1.
5. The preparation method according to claim 2, characterized in that: The feeding ratio of the second batch of CDI and the third batch of alkaline reagent is calculated based on the compound of formula III, and the molar ratio of the second batch of CDI, the third batch of alkaline reagent and the compound of formula III is (1.0-1.5):(2-2.5):
1.
6. A one-pot preparation method of an S-217622 intermediate, wherein the S-217622 intermediate is a compound of formula I, characterized in that: When the preparation method according to any one of claims 1 to 5 is used to react to obtain the compound of formula II, an inorganic base and a 2,4,5-trifluoro-halogenated benzyl compound are directly added to the reaction system without post-treatment to carry out an alkylation reaction to obtain a compound of formula I; 7. The preparation method according to claim 6, characterized in that: The inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.
8. The preparation method according to claim 7, characterized in that: The inorganic base is selected from sodium carbonate or potassium carbonate.
Citation Information
Patent Citations
Preparation method of oral medicine S-217622 for treating new coronal pneumonia
CN114644621A